US5536728A - 4-acylaminopyridine derivative - Google Patents
4-acylaminopyridine derivative Download PDFInfo
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- US5536728A US5536728A US08/355,181 US35518194A US5536728A US 5536728 A US5536728 A US 5536728A US 35518194 A US35518194 A US 35518194A US 5536728 A US5536728 A US 5536728A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
- C07D219/08—Nitrogen atoms
- C07D219/10—Nitrogen atoms attached in position 9
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to a novel 4-acylaminopyridine derivative and a pharmaceutically acceptable acid-added salt thereof useful for activating a malfunctioned cholinergic neuron.
- 9-acylaminotetrahydroacridines 9-acylaminotetrahydroacridine is described in Journal of Chemical Society, 634(1947) and 9-chloroacetylaminotetrahydroacridine and 9-dietylaminoacetylaminotetrahydroacridine are described in Chem. listy, 51, 1907(1957).
- 9-Diemethylaminoacetylaminotetrahydroacridine is described to have a local anesthetic action.
- the present inventors have made various and extensive studies so as to provide a medicine effective for treatment of senile dementia including Alzheimer's disease. As the result thereof, it has been found that a particular 4-acylaminopyridine derivative and a pharmaceutically acceptable acid-added salt thereof can improve disturbances of memory such as Alzheimer's disease by a mechanism different from that of a conventionally known compound having an antiacetylcholinesterase activity. The present invention has been accomplished based on this finding.
- the present invention provides a 4-acylaminopyridine derivative represented by the following formula (I): ##STR2## wherein R 1 represents a C 2 -C 6 alkyl group or a group represented by the following formula (II): ##STR3## wherein each of R 2 and R 3 independently represents a hydrogen atom, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group or ##STR4## wherein each of R 4 and R 5 independently represents a hydrogen atom or C 1 -C 6 alkyl group, or R 2 and R 3 together with the nitrogen atom to which both R 2 and R 3 are attached represent ##STR5## wherein R 6 represents a hydrogen atom or C 1 -C 6 alkyl group, and n represents 0 or an integer from 1 to 3; ##STR6## wherein R 7 represents a hydrogen atom, C 1 -C 6 alkyl group or halogen atom, ##STR7## wherein each of R 8 and R 9 independently represents a
- the present invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically effective amount of a 4-acylaminopyridine derivative represented by the formula (I) or a pharmaceutically acceptable acid-added salt thereof, and a pharmaceutically acceptable adjuvant.
- the present invention still further provides a process for producing a 4-acylaminopyridine derivative represented by the formula (I) and a pharmaceutically acceptable acid-added salt thereof.
- the 4-acylaminopyridine derivative according to the present invention is represented by the formula (I) shown above.
- C 2 -C 6 alkyl group (alkyl group having 2 to 6 carbon atoms) represented by R 1 , ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group and n-hexyl group may be mentioned.
- a C 2 -C 4 alkyl group is particularly preferable.
- Examples of C 1 -C 6 alkyl group represented by each of R 2 to R 7 are methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group and n-hexyl group. Among these, a C 1 -C 4 alkyl group is preferable.
- C 3 -C 6 cycloalkyl group represented by each of R 2 and R 3 cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group may be mentioned.
- a halogen atom represented by R 7 is exemplified by fluorine atom, chlorine atom, bromine atom and iodine atom.
- C 1 -C 4 alkyl group represented by each of R 8 to R 13 methyl group, ethyl group; n-propyl group, isopropyl group, n-butyl group, sec-butyl group and tert-butyl group may be mentioned.
- R 1 represents a C 2 -C 6 alkyl group or a group represented by the following formula (II): ##STR16## wherein R 2 represents a hydrogen atom or C 1 -C 8 alkyl group, R 3 represents a hydrogen atom, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group or ##STR17## wherein each of R 4 and R 5 independently represents a hydrogen atom or C 1 -C 6 alkyl group, or R 2 and R 3 together with the nitrogen atom to which both R 2 and R 3 are attached represent ##STR18## wherein R 6 represents a hydrogen atom or C 1 -C 6 alkyl group, and n represents 0 or an integer from 1 to 3; ##STR19## wherein R 7 represents a hydrogen atom, C 1 -C 6 alkyl group or halogen atom, ##STR20## wherein each of R 8 and R
- the acid-added salt of the compound represented by the formula (I) is preferred to be pharmaceutically and physiologically acceptable.
- inorganic acid-added salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate
- organic acid-added salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate and camphorsulfonate may be mentioned.
- the compound represented by the formula (I) and the acid-added salt thereof can be present in the form of hydrate or solvate. These hydrate and solvate are also included in the compound of the present invention.
- the compound represented by the formula (I) is produced by, for example, any of the following processes (1) to (5). ##STR25##
- a halogen solvent such as dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane or an inert polar solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone may be preferably used.
- the reaction may be carried out at a temperature from 0° to 120° C., preferably 20° to 80° C. ##STR27##
- the compound of the present invention represented by the formula (I 2 ) can be produced by reacting a compound of the formula (III) with excess trichloroacetyl chloride (reaction (a)) to obtain and isolate a trichloroacetamide compound of the formula (VI), and then reacting the compound of the formula (VI) with an amine of the formula (VII) or acetate thereof (reaction (b)).
- the reaction (a) is carried out by using trichloroacetyl chloride also as the solvent at a temperature from 80° to 115° C., preferably from 100° to 115° C.
- the reaction (b) is carried out preferably in an inert solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.
- the reaction temperature is from 0° to 100° C., preferably from 0° to 50° C. when the amine is used, and from 50° to 160° C., preferably from 100° to 150° C. when the acetate of the amine is used.
- the compound of the formula (III) is dissolved in an inert solvent such as methylene chloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, benzene, toluene, xylene, tetrahydrofuran and dioxane, then, a phosgene compound such as ditrichloromethyl carbonate, phosgene and trichloromethyl chloroformate is added to the solution, followed by the addition of a tertiary amine such as triethylamine. The thus obtained solution is added dropwise to a solvent containing the amine represented by the formula (VII) to give the compound represented by the formula (I 1 ).
- an inert solvent such as methylene chloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, benzene, toluene, xylene, tetrahydrofuran and dioxane
- the solvent for dissolving the amine represented by the formula (VII) tetrahydrofuran, dioxane, acetonitrile and alcohols are preferable, and it is possible to use a mixed solvent of water with at least one of the above-described solvents, if necessary.
- the addition of the phosgene compound and the addition of the tertiary amine are carried out at a temperature from -10° to 50° C., preferably from 0° to 30° C.
- the reaction with the amine represented by the formula (VII) is carried out at a temperature from -20° to 30° C., preferably from -10° to 20° C.
- Examples of the reactive derivatives of the compound of the formula (VIII) are preferably symmetric acid anhydrides or acid halides, particularly acid chloride.
- the reaction is carried out in the presence of of an inert solvent such as benzene, toluene, xylene, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., or by using excessive amounts of symmetric acid anhydrides or acid halides as a solvent.
- an inert solvent such as benzene, toluene, xylene, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc.
- a tertiary amine such as pyridine may be preferably used.
- the reaction is carried out at a temperature in the range of 30° to 150° C., preferably 50° to 120° C.
- reaction is carried out at a temperature in the range of 10° to 80° C., preferably 30° to 60° C.
- an acyl halide compound of the formula (X) is reacted with the compound of the formula (III) to obtain the compound of the formula (XI) [step (a)]. Then, to the compound of the formula (XI), the compound of the formula (XII) is reacted, or else a compound which is a sodium salt obtained by treating the compound of the formula (XIII) with sodium hydride [step (b)], the corresponding compound (I) can be obtained.
- the step (a) is carried out by using an excessive amount of acyl halide also as the solvent, or by using an inert solvent such as benzene, toluene, xylene, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., at a temperature in the range of 50° to 150° C., preferably 70° to 120° C.
- an inert solvent such as benzene, toluene, xylene, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc.
- the step (b) is carried out by using an excessive amount of amine also as the solvent, or by using an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butenol, etc., or a solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, etc., at a temperature in the range of 0° to 150° C., preferably 20° to 100° C.
- an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butenol, etc.
- a solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, etc.
- the reaction is carried out by using a solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, etc., at a temperature in the range of 0° to 120° C., preferably 20° to 80° C.
- a solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, etc.
- R 1 is a group represented by the formula (II) and R 2 and R 3 together with the nitrogen atom to which both R 2 and R 3 are attached represent ##STR46## wherein R 6 is the same as defined above, i.e. the compound represented by the formula (I 6 ), can be produced according to the following reaction scheme. ##STR47## wherein ##STR48## and R 6 are the same as defined above and R 20 represents a C 1 -C 4 alkyl group.
- the compound of the formula (I 6 ) can be obtained by heating the compound of the formula (XIV) together with 1 to 10 equivalents of urea in the presence or absence of a solvent.
- the compound of the formula (XIV), the starting material can be obtained by the process described in process (4).
- an inert polar solvent such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide and N-methylpyrrolidone is preferred.
- the reaction temperature is from 120° to 190° C., preferably from 140° to 170° C.
- the starting compound represented by the formula (III) can be easily synthesized by, for example, the methods described in (a) Tetrahedron Letters, 1277(1963), (b) Collect. Czech. Chem. Commun., 42, 2802(1977), and (c) Acta Chemica Scandinavica, B, 33, 313(1979) and similar methods thereto.
- the acid-added salt of the compound represented by the formula (I) can be easily obtained by a known method to prepare an acid-added salt of a quinoline or pyridine based compound.
- the compound of the present invention is used as a therapeutic medicine by administrating it singly or in the form of a mixture with a pharmaceutically accept, able carrier.
- the composition is determined based on the solubility and property of the compound to be used as the active ingredient, the administration route and dosage regimen.
- the compound of the present invention may be orally administered in the form of granule, subtilized granule, powder, tablet, hard capsule, soft capsule, syrup, emulsion, suspension and solution.
- the compound of the present invention may be also administered intravenously, intramuscularly or subcutaneously by injection.
- the compound of the present invention may be prepared to an injectable powder and injected after dissolving or suspending in an appropriate solvent when used.
- an organic or inorganic, solid or liquid carrier or diluent which is suitable for oral, intestinal, parenteral or local administration, together with the compound of the present invention.
- a vehicle for a solid preparation lactose, sucrose, starch, talc, cellulose, dextrin, kaolin and calcium carbonate are usable.
- a liquid preparation for oral administration i.e. emulsion, syrup, suspension, solution, etc., contains a usual diluent such as water, vegetable oil, etc.
- the liquid preparation can contain an auxiliary such as a hnmectant, suspending agent, sweetening agent, aromatic, coloring agent, preservative etc. in addition to the inert diluent.
- the liquid preparation may be encapsulated in an absorbable wall substance such as gelatin.
- an absorbable wall substance such as gelatin.
- a solvent or a suspending agent used for preparing a parenteral preparation such as an injection preparation, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate and lecithin may be mentioned.
- the preparation may be carried out by an ordinary method.
- the daily clinical dosage of the compound of the present invention in oral administration is usually 1 to 1000 mg, preferably 1 to 100 mg for an adult. It is preferable to appropriately increase or decrease the dose depending upon the age of patient, condition of disease, condition of patient, and whether or not another medicine is administered.
- the daily dose of the compound of the present invention may be administered at once, or in two or three portions with appropriate interval. Intermittent administration thereof is also applicable.
- the daily dosage of the compound of the present invention in injection is 0.1 to 100 mg, preferably 0.1 to 50 mg for an adult.
- the compound of the present invention can reactivate the presynaptic site of the cholinergic neuron to enhance the neurotransmission. More precisely, the compound of the present invention improves the reduced high-affinity choline-uptake in the hippocampak synaptosome of a rat treated with AF64A (ethylcholine aziridinium ion; J. Pharmacol. Exp. Ther., 222, 140(1982) and Neuropharmacol., 26, 361(1982)) intra-cerebroventricularly (Test Example 1 below). This kind of action is not observed in 9-aminotetrahydroacridine.
- AF64A ethylcholine aziridinium ion
- the compound of the present invention is very low in toxicity and scarcely produces side effect in comparison with 9-aminotetrahydroacridine, and therefore, the compound of the present invention can be a useful medicine for treating disturbances of memory such as Alzheimer's disease.
- the compound of the present invention represented by the formula (I) is a pharmaceutically active and valuable compound. Especially, the compound of the present invention is useful as a medicine for treating disturbances of memory such as senile dementia and Alzheimer's disease, since it has an action on the activating malfunctioned cholinergic neuron.
- senile dementia in particular, Alzheimer's disease
- the function of the cholinergic neuron in the bran is decreased, and it is recognized that there is a good correlation between the deficit in the cholinergic neuron and the degree of disturbances in memory.
- AF64A causes long-term malfunction selectively on cholinergic neuron, and disturbance of memory and learning is observed in a rat to which AF64A is administered.
- a rat is used as a good model of Alzheimer's disease. Therefore, from the above pharmacological results, the compound of the present invention is considered to be useful for treating senile dementia including Alzheimer's disease.
- the solvent was evaporated under a reduced pressure and 100 ml of chloroform, 100 ml of water and 5 ml of concentrated ammonia water were added, followed by stirring.
- the chloroform layer was dried over anhydrous sodium sulfate.
- the chloroform solution was evaporated.
- the obtained product was purified by silica gel column chromatography (chloroform-methanol) and was recrystallized from chloroform-diethyl ether to obtain 5.11 g of the titled compound having the melting point of 200° to 202° C.
- the titled compound having the melting point of 245° to 246° C. was obtained in the same way as in Example 10 except for using isobutyric anhydride in place of n-butyric anhydride.
- Example 38 Into 12 ml of 1N aqueous solution of sodium hydroxide, was added 2 g of the compound obtained in Example 38 at room temperature, and the reaction was continued for 2 hours. To the reaction mixture, was added 15 ml of 1N hydrochloric acid at a temperature not higher than 15° C. to precipitate white crystals. The crystals were collected by filtration, washed with water and dried to obtain 1.42 g of the titled compound having the melting point of 238° to 242° C. (decomposed).
- the chloroform layer was dried over anhydrous sodium sulfate and concentrated to a volume of about 100 ml.
- the chloroform solution was added with 40 ml of n-heptane and cooled, followed by filtration to obtain 8.2 g of the titled compound having the melting point of 233° to 236° C.
- the reaction mixture was evaporated to dryness under a reduced pressure, then, 100 ml of chloroform, 30 ml of water and 5 ml of concentrated ammonia water were added, followed by stirring.
- the chloroform layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (chloroform-methanol), followed by recrystallization from ethyl acetate to obtain 1.52 g of titled compound having the melting point of 141° to 144° C.
- HACU high-affinity choline uptake ability
- AF64A was prepared from AF64 in accordance with the method of Fischer et al. (J. Pharmacol. Exp. Ther., 222, 140(1982)). AF64A (1.5 nmol/1.5 ⁇ l/side) was injected into both the lateral ventricles of a rat. One week after, the rat was decapitated and only the hippocampus was taken out. The hippocampus was homogenized with 0.32M of sucrose and centrifuged at 1000 g for 10 minutes. The supernatant thereof was further centrifuged at 20000 g for 20 minutes to obtain a crude synapse fraction. The crude synapse fraction was added with a compound of the present invention and incubated at 37° C.
Abstract
A novel 4-acylaminopyridine derivative represented by the following formula (I) is disclosed. <IMAGE> (I) The 4-acylaminopyridine derivative of the present invention is useful as a medicine for treating disturbances of memory such as senile dementia and Alzheimer's disease, since it has an action of directly activating malfunctioned cholinergic neuron.
Description
This is a division of application Ser. No. 08/115,257 filed on Sep. 2, 1993, now U.S. Pat. No. 5,397,785, which is a continuation of Ser. No. 07/853,519 filed on Mar. 18, 1992, now abandoned, which is a continuation of Ser. No. 07/610,059 filed on Nov. 7, 1990 now abandoned.
The present invention relates to a novel 4-acylaminopyridine derivative and a pharmaceutically acceptable acid-added salt thereof useful for activating a malfunctioned cholinergic neuron.
As a therapeutic treatment for various disturbances of memory such as Alzheimer's disease characterized by malfunction of a cholinergic neuron, has been made an attempt to increase the acetylcholine content in the brain by using an antiacetylcholinesterase. For example, investigation on the use of physostigmine is reported in Neurology, 8, 397(1978). Japanese Patent Application Laid-Open (KOKAI) Nos. 61-148154(1986), 63-141980(1988), 63-225358(1988), 63-238063(1988), 63-239271(1988),63-284175(1988), 63-297367(1988), 64-73(1989) and 1-132566(1989), EP-A-268871 and International Publication of PCT 88/02256 report that a particular derivative of 9-anminotetrahydroacridine has an antiacetylcholinesterase activity and is therefore useful for treatment of Alzheimer's disease.
Summers reports in The New England Journal of Medicine, 315, 1241(1986) that 9-amino-1,2,3,4-tetrahydroacridine (tacrine) is effective for treatment of Alzheimer's disease when used together with lecithin. However, improvement is still insufficient and it produces undesirable side effects, and therefore, a new therapeutic treatment has been demanded.
As examples of the known 9-acylaminotetrahydroacridines, 9-acylaminotetrahydroacridine is described in Journal of Chemical Society, 634(1947) and 9-chloroacetylaminotetrahydroacridine and 9-dietylaminoacetylaminotetrahydroacridine are described in Chem. listy, 51, 1907(1957). 9-Diemethylaminoacetylaminotetrahydroacridine is described to have a local anesthetic action. In Journal of Medicinal Chemistry, 18, 1056(1975), structure-activity correlation on antiacetylcholinesterase activity of 9-aminotetrahydroacridine derivatives and it is reported that the activity of 9-acetylaminotetrahydroacridine and 9-benzoylaminotetrahydroacridine is 1/1000 of the activity of 9-aminotetrahydroacridine. Some of Japanese Patent Application Laid-Open (KOKAI) Nos. 63-166881(1988), 63-203664(1988), 63-238063(1988), 63-239271(1988), 63-284175(1988), 64-73(1989) and 1-132566(1989) claims a 9-acylaminotetrahydroacridine derivative, however, none of them disclose expressly the synthesis of nor a pharmaceutical activity of a compound having a 9-acylamino group.
The present inventors have made various and extensive studies so as to provide a medicine effective for treatment of senile dementia including Alzheimer's disease. As the result thereof, it has been found that a particular 4-acylaminopyridine derivative and a pharmaceutically acceptable acid-added salt thereof can improve disturbances of memory such as Alzheimer's disease by a mechanism different from that of a conventionally known compound having an antiacetylcholinesterase activity. The present invention has been accomplished based on this finding.
The present invention provides a 4-acylaminopyridine derivative represented by the following formula (I): ##STR2## wherein R1 represents a C2 -C6 alkyl group or a group represented by the following formula (II): ##STR3## wherein each of R2 and R3 independently represents a hydrogen atom, C1 -C6 alkyl group, C3 -C6 cycloalkyl group or ##STR4## wherein each of R4 and R5 independently represents a hydrogen atom or C1 -C6 alkyl group, or R2 and R3 together with the nitrogen atom to which both R2 and R3 are attached represent ##STR5## wherein R6 represents a hydrogen atom or C1 -C6 alkyl group, and n represents 0 or an integer from 1 to 3; ##STR6## wherein R7 represents a hydrogen atom, C1 -C6 alkyl group or halogen atom, ##STR7## wherein each of R8 and R9 independently represents a hydrogen atom or C1 -C4 alkyl group, ##STR8## wherein each of R10 and R11 independently represents a hydrogen atom or a C1 -C4 alkyl group, ##STR9## wherein each of R12 and R13 independently represents a hydrogen atom or C1 -C4 alkyl group or R12 and R13 may be combined together to form a C2 -C6 alkylene group, ##STR10## with the proviso that when R1 is a C2 -C6 alkyl group or a group represented by the formula (II) wherein one of R2 and R3 is a hydrogen atom or C1 -C6 alkyl group and the other of R2 and R3 is a hydrogen atom or -CH2 COOR5 wherein R5 is the same as defined above, or R2 and R3 together with the nitrogen atom to which both R2 and R3 are attached represent ##STR11## and n is 1 or 2, ##STR12## wherein R7 is the same as defined above, or is not ##STR13## wherein R9 is the same as defined above, and ##STR14## wherein R12 represents a hydrogen atom or C1 -C4 alkyl group or is not ##STR15## and a pharmaceutically acceptable acid-added salt thereof.
The present invention further provides a pharmaceutical composition comprising a pharmaceutically effective amount of a 4-acylaminopyridine derivative represented by the formula (I) or a pharmaceutically acceptable acid-added salt thereof, and a pharmaceutically acceptable adjuvant.
The present invention still further provides a process for producing a 4-acylaminopyridine derivative represented by the formula (I) and a pharmaceutically acceptable acid-added salt thereof.
The 4-acylaminopyridine derivative according to the present invention is represented by the formula (I) shown above.
In the formula (I), as examples of C2 -C6 alkyl group (alkyl group having 2 to 6 carbon atoms) represented by R1, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group and n-hexyl group may be mentioned. Among these, a C2 -C4 alkyl group is particularly preferable.
Examples of C1 -C6 alkyl group represented by each of R2 to R7 are methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group and n-hexyl group. Among these, a C1 -C4 alkyl group is preferable.
As C3 -C6 cycloalkyl group represented by each of R2 and R3, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group may be mentioned.
A halogen atom represented by R7 is exemplified by fluorine atom, chlorine atom, bromine atom and iodine atom.
As examples of C1 -C4 alkyl group represented by each of R8 to R13, methyl group, ethyl group; n-propyl group, isopropyl group, n-butyl group, sec-butyl group and tert-butyl group may be mentioned.
In the present invention, among the compounds represented by the formula (I), is preferred a compound wherein R1 represents a C2 -C6 alkyl group or a group represented by the following formula (II): ##STR16## wherein R2 represents a hydrogen atom or C1 -C8 alkyl group, R3 represents a hydrogen atom, C1 -C6 alkyl group, C3 -C6 cycloalkyl group or ##STR17## wherein each of R4 and R5 independently represents a hydrogen atom or C1 -C6 alkyl group, or R2 and R3 together with the nitrogen atom to which both R2 and R3 are attached represent ##STR18## wherein R6 represents a hydrogen atom or C1 -C6 alkyl group, and n represents 0 or an integer from 1 to 3; ##STR19## wherein R7 represents a hydrogen atom, C1 -C6 alkyl group or halogen atom, ##STR20## wherein each of R8 and R9 independently represents a hydrogen atom or C1 -C4 alkyl group, or ##STR21## wherein each of R10 and R11 independently represents a hydrogen atom or a C1 -C4 alkyl group; and ##STR22## wherein each of R12 and R13 independently represents a hydrogen atom or C1 -C4 alkyl group or R12 and R13 may be combined together to fore a C2 -C6 alkylene group, or ##STR23##
More preferred is a compound wherein ##STR24## wherein R7 to R11 are the same as defined above.
The acid-added salt of the compound represented by the formula (I) is preferred to be pharmaceutically and physiologically acceptable. For example, inorganic acid-added salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate, and organic acid-added salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate and camphorsulfonate may be mentioned. The compound represented by the formula (I) and the acid-added salt thereof can be present in the form of hydrate or solvate. These hydrate and solvate are also included in the compound of the present invention.
A process for producing the compound of the present invention will now be explained.
The compound represented by the formula (I) is produced by, for example, any of the following processes (1) to (5). ##STR25##
In the above reaction scheme, ##STR26## in the formulae (III) and (V) are the same as defined above, and R14 in the formulae (IV) and (V) represents a C1 -C6 alkyl group or C3 -C6 cycloalkyl group. Through the process (1), the compound of the present invention represented by the formula (V) can be produced by reacting a primary aromatic amine of the formula (III) with an isocyanate compound of the formula (IV).
As the reaction solvent, a halogen solvent such as dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane or an inert polar solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone may be preferably used.
The reaction may be carried out at a temperature from 0° to 120° C., preferably 20° to 80° C. ##STR27##
In the above reaction scheme, ##STR28## in the formulae (III), (VI) and (I1) and R2 and R3 in the formulae (VII) and (I1) are the same as defined above. Through the process (2), the compound of the present invention represented by the formula (I2) can be produced by reacting a compound of the formula (III) with excess trichloroacetyl chloride (reaction (a)) to obtain and isolate a trichloroacetamide compound of the formula (VI), and then reacting the compound of the formula (VI) with an amine of the formula (VII) or acetate thereof (reaction (b)).
The reaction (a) is carried out by using trichloroacetyl chloride also as the solvent at a temperature from 80° to 115° C., preferably from 100° to 115° C.
The reaction (b) is carried out preferably in an inert solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc. The reaction temperature is from 0° to 100° C., preferably from 0° to 50° C. when the amine is used, and from 50° to 160° C., preferably from 100° to 150° C. when the acetate of the amine is used. ##STR29##
In the above reaction scheme, ##STR30## in the formulae (III) and (I1), and R2 and R3 in the formulae (VII) and (I1) are the same as defined above. Through the process (3), the compound of the present invention represented by the formula (I1) can be produces. More in detail, the compound of the formula (III) is dissolved in an inert solvent such as methylene chloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, benzene, toluene, xylene, tetrahydrofuran and dioxane, then, a phosgene compound such as ditrichloromethyl carbonate, phosgene and trichloromethyl chloroformate is added to the solution, followed by the addition of a tertiary amine such as triethylamine. The thus obtained solution is added dropwise to a solvent containing the amine represented by the formula (VII) to give the compound represented by the formula (I1). As the solvent for dissolving the amine represented by the formula (VII), tetrahydrofuran, dioxane, acetonitrile and alcohols are preferable, and it is possible to use a mixed solvent of water with at least one of the above-described solvents, if necessary.
In the above reaction (c), the addition of the phosgene compound and the addition of the tertiary amine are carried out at a temperature from -10° to 50° C., preferably from 0° to 30° C. The reaction with the amine represented by the formula (VII) is carried out at a temperature from -20° to 30° C., preferably from -10° to 20° C.
(1) By reacting the compound represented by the formula (III): ##STR31## wherein ##STR32## have the same meanings as defined in the above formula (I), with a reactive derivative of the compound represented by the formula (VIII): ##STR33## wherein R15 represents a C2 -C6 alkyl group, the compound represented by the formula (I2) of the present invention can be obtained. ##STR34## wherein ##STR35## and R15 have the same meanings as defined above.
Examples of the reactive derivatives of the compound of the formula (VIII) are preferably symmetric acid anhydrides or acid halides, particularly acid chloride. The reaction is carried out in the presence of of an inert solvent such as benzene, toluene, xylene, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., or by using excessive amounts of symmetric acid anhydrides or acid halides as a solvent. When the symmetric acid anhydrides are used, a tertiary amine such as pyridine may be preferably used. The reaction is carried out at a temperature in the range of 30° to 150° C., preferably 50° to 120° C.
(2) After processing the compound represented by the above formula (III) with an equimolar Amount or more of sodium hydride to prepare a sodium salt, reacting it with an ester compound represented by the formula (IX): ##STR36## wherein R16 represents ##STR37## (wherein i represents an integer from 1 to 3), and R17 represents a methyl group or an ethyl group, to obtain the compound represented by the formula (I3): ##STR38## wherein ##STR39## and R16 have the same meanings as defined above.
As the solvent, preferred are tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, etc. The reaction is carried out at a temperature in the range of 10° to 80° C., preferably 30° to 60° C. ##STR40## wherein X represents a chlorine atom or a bromine atom; i represents 1, 2 or 3; ##STR41## have the same meanings as defined in the formula (I); R18 in the formula (XII) represents a C1 -C6 alkyl group or ##STR42## (wherein R4 and R5 have the same meanings as defined in the formula (I); R19 in the formula (XIII) represents ##STR43##
By the above two steps of the reaction formulae, the compound of the formula (I4) or (I5) can be synthesized. ##STR44##
In the above formulae (I4) and (I5), ##STR45## R18, R19 and i have the same meanings as defined above.
That is, an acyl halide compound of the formula (X) is reacted with the compound of the formula (III) to obtain the compound of the formula (XI) [step (a)]. Then, to the compound of the formula (XI), the compound of the formula (XII) is reacted, or else a compound which is a sodium salt obtained by treating the compound of the formula (XIII) with sodium hydride [step (b)], the corresponding compound (I) can be obtained.
The step (a) is carried out by using an excessive amount of acyl halide also as the solvent, or by using an inert solvent such as benzene, toluene, xylene, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., at a temperature in the range of 50° to 150° C., preferably 70° to 120° C.
The step (b) is carried out by using an excessive amount of amine also as the solvent, or by using an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butenol, etc., or a solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, etc., at a temperature in the range of 0° to 150° C., preferably 20° to 100° C. When the sodium salt of the compound of the formula (XIII) is reacted, the reaction is carried out by using a solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, etc., at a temperature in the range of 0° to 120° C., preferably 20° to 80° C.
The compound where R1 is a group represented by the formula (II) and R2 and R3 together with the nitrogen atom to which both R2 and R3 are attached represent ##STR46## wherein R6 is the same as defined above, i.e. the compound represented by the formula (I6), can be produced according to the following reaction scheme. ##STR47## wherein ##STR48## and R6 are the same as defined above and R20 represents a C1 -C4 alkyl group.
In more detail, the compound of the formula (I6) can be obtained by heating the compound of the formula (XIV) together with 1 to 10 equivalents of urea in the presence or absence of a solvent.
The compound of the formula (XIV), the starting material, can be obtained by the process described in process (4).
As the solvent for producing the compound of the formula (I6), an inert polar solvent such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide and N-methylpyrrolidone is preferred.
The reaction temperature is from 120° to 190° C., preferably from 140° to 170° C.
The starting compound represented by the formula (III) can be easily synthesized by, for example, the methods described in (a) Tetrahedron Letters, 1277(1963), (b) Collect. Czech. Chem. Commun., 42, 2802(1977), and (c) Acta Chemica Scandinavica, B, 33, 313(1979) and similar methods thereto.
It is also possible to synthesize the starting compound (III) in accordance with the methods described in Japanese Patent Application Laid-Open (KOKAI) Nos. 61-148154(1986), 63-141980(1988), 63-166881(1988), 63-203664(1988), 63-225358(1988), 63-238063(1988), 63-239271(1988), 63-297367(1988), 64-73(1989), 1-132566(1989) and EP-A-268871.
The acid-added salt of the compound represented by the formula (I) can be easily obtained by a known method to prepare an acid-added salt of a quinoline or pyridine based compound.
Some of the starting compound represented by the formula (III) for producing the compound of the present invention, which were produced according to the methods described in the above references are shown in Table 1 below.
TABLE 1
______________________________________
##STR49##
##STR50##
##STR51##
##STR52##
##STR53##
______________________________________
1
##STR54##
##STR55## 199˜200
2
##STR56##
##STR57## 162˜163
3
##STR58##
##STR59## 203˜204
4
##STR60##
##STR61## 141˜143
5
##STR62##
##STR63## 201˜204
6
##STR64##
##STR65## 206˜207
7
##STR66##
##STR67## 156˜158
8
##STR68##
##STR69## 213˜214
9
##STR70##
##STR71## 238˜242
10
##STR72##
##STR73## 138˜139
______________________________________
The compound of the present invention is used as a therapeutic medicine by administrating it singly or in the form of a mixture with a pharmaceutically accept, able carrier. The composition is determined based on the solubility and property of the compound to be used as the active ingredient, the administration route and dosage regimen. For example, the compound of the present invention may be orally administered in the form of granule, subtilized granule, powder, tablet, hard capsule, soft capsule, syrup, emulsion, suspension and solution. The compound of the present invention may be also administered intravenously, intramuscularly or subcutaneously by injection. The compound of the present invention may be prepared to an injectable powder and injected after dissolving or suspending in an appropriate solvent when used.
It is possible to use an organic or inorganic, solid or liquid carrier or diluent, which is suitable for oral, intestinal, parenteral or local administration, together with the compound of the present invention. As a vehicle for a solid preparation, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin and calcium carbonate are usable. A liquid preparation for oral administration, i.e. emulsion, syrup, suspension, solution, etc., contains a usual diluent such as water, vegetable oil, etc. The liquid preparation can contain an auxiliary such as a hnmectant, suspending agent, sweetening agent, aromatic, coloring agent, preservative etc. in addition to the inert diluent. The liquid preparation may be encapsulated in an absorbable wall substance such as gelatin. As a solvent or a suspending agent used for preparing a parenteral preparation such as an injection preparation, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate and lecithin may be mentioned. The preparation may be carried out by an ordinary method.
The daily clinical dosage of the compound of the present invention in oral administration is usually 1 to 1000 mg, preferably 1 to 100 mg for an adult. It is preferable to appropriately increase or decrease the dose depending upon the age of patient, condition of disease, condition of patient, and whether or not another medicine is administered. The daily dose of the compound of the present invention may be administered at once, or in two or three portions with appropriate interval. Intermittent administration thereof is also applicable.
The daily dosage of the compound of the present invention in injection is 0.1 to 100 mg, preferably 0.1 to 50 mg for an adult.
Although the antiacetylcholinesterase activity of the compound represented by the formula (I) is 1/100 of that of known 9-aminotetrahydroacridine, the compound of the present invention can reactivate the presynaptic site of the cholinergic neuron to enhance the neurotransmission. More precisely, the compound of the present invention improves the reduced high-affinity choline-uptake in the hippocampak synaptosome of a rat treated with AF64A (ethylcholine aziridinium ion; J. Pharmacol. Exp. Ther., 222, 140(1982) and Neuropharmacol., 26, 361(1982)) intra-cerebroventricularly (Test Example 1 below). This kind of action is not observed in 9-aminotetrahydroacridine.
Further, the compound of the present invention is very low in toxicity and scarcely produces side effect in comparison with 9-aminotetrahydroacridine, and therefore, the compound of the present invention can be a useful medicine for treating disturbances of memory such as Alzheimer's disease.
The compound of the present invention represented by the formula (I) is a pharmaceutically active and valuable compound. Especially, the compound of the present invention is useful as a medicine for treating disturbances of memory such as senile dementia and Alzheimer's disease, since it has an action on the activating malfunctioned cholinergic neuron.
In senile dementia, in particular, Alzheimer's disease, the function of the cholinergic neuron in the bran is decreased, and it is recognized that there is a good correlation between the deficit in the cholinergic neuron and the degree of disturbances in memory.
As reported by Fisher (J. Pharmacol. Exp. Ther., 222, 140(1982)) and Leventer (Neuropharmacol, 26, 361(1987)), AF64A causes long-term malfunction selectively on cholinergic neuron, and disturbance of memory and learning is observed in a rat to which AF64A is administered. Such a rat is used as a good model of Alzheimer's disease. Therefore, from the above pharmacological results, the compound of the present invention is considered to be useful for treating senile dementia including Alzheimer's disease.
The present invention will be explained in more detail with reference to the following examples, but it is to be understood that the present invention is not restricted to the following examples and any modification is possible within the scope of the present invention.
To 4.37 g of 4-amino-3-methyl -5,6,7,8-tetrahydrothieno[2,3-b]quinoline, were added 8 ml of pyridine and 12.7 g of n-butyric anhydride and the mixture was refluxed for 13 hours. The reaction mixture was evaporated to dryness under a reduced pressure, and dissolved in 170 ml of methanol and 40 ml of ethanol. To the solution, was added 70 ml of concentrated ammonia water and the reaction was carried out at 65° C. for 1.5 hours.
The solvent was evaporated under a reduced pressure and 100 ml of chloroform, 100 ml of water and 5 ml of concentrated ammonia water were added, followed by stirring. The chloroform layer was dried over anhydrous sodium sulfate.
The chloroform solution was evaporated. The obtained product was purified by silica gel column chromatography (chloroform-methanol) and was recrystallized from chloroform-diethyl ether to obtain 5.11 g of the titled compound having the melting point of 200° to 202° C.
Each of the compounds listed in Table 2 was synthesized in the same manner as in Example 1.
TABLE 2
______________________________________
##STR74##
##STR75##
##STR76##
##STR77##
##STR78##
______________________________________
2
##STR79##
##STR80## 201˜203
3
##STR81##
##STR82## 192˜194
4
##STR83##
##STR84## 183˜184
5
##STR85##
##STR86## 175˜176
6
##STR87##
##STR88## 168˜170
7
##STR89##
##STR90## 164˜165
8
##STR91##
##STR92## 205˜206
9
##STR93##
##STR94## 188˜190
10
##STR95##
##STR96## 204˜206
11
##STR97##
##STR98## 88˜91
12
##STR99##
##STR100## 193˜194
13
##STR101##
##STR102## 159˜161
______________________________________
The titled compound having the melting point of 245° to 246° C. was obtained in the same way as in Example 10 except for using isobutyric anhydride in place of n-butyric anhydride.
Into a suspension of 1.26 g of sodium hydride (60% content) in 15 ml of N-methylpyrrolidone, was added 3.28 g of 4-amino-3-methyl -5,6,7,8-tetrahydrothieno[2,3-b]quinoline at room temperature. The mixture was heated to 50° C. and stirred for 40 minutes. Thereafter, 4.72 g of methyl 2-oxo-1-pyrrolidine acetate was added dropwise to the mixture at 50° C. over a period of 30 minutes. After the stirring at 50° C. for 20 minutes, the mixture was cooled to 15° C. and poured into 130 ml aqueous solution containing 13.5 g of ammonium chloride.
After extraction of the solution with 100 ml of chloroform, the extract was dried over anhydrous sodium sulfate, followed by evaporation to dryness. The resultant product was added with ethyl acetate, pulverized and filtered. The crude crystals were recrystallized from chloroform-ethyl acetate to obtain 4.31 g of the titled compound having the melting point of 244° to 246° C.
Each of the compounds listed in Table 3 was synthesized in the same way is in Example 15.
TABLE 3
______________________________________
##STR103##
##STR104##
##STR105##
##STR106##
##STR107##
______________________________________
16
##STR108##
##STR109## 217˜220
17
##STR110##
##STR111## 222˜225
18
##STR112##
##STR113## 244˜246
19
##STR114##
##STR115## 203˜204
20
##STR116##
##STR117## 192˜194
21
##STR118##
##STR119## 168˜170
22
##STR120##
##STR121## 161˜163 hydrochloride
23
##STR122##
##STR123## 216˜218
24
##STR124##
##STR125## 210˜212
25
##STR126##
##STR127## 213˜215
26
##STR128##
##STR129## 189˜191
27
##STR130##
##STR131## 193˜195
28
##STR132##
##STR133## 216˜217
29
##STR134##
##STR135## 159˜161
______________________________________
A mixture of 8.17 g of 4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinoline and 90 ml of trichloroacetyl chloride was refluxed for 4 hours. The mixture was cooled to 25° C. and 30 ml of 1,2-dichloroethane was added thereto. The crystals were filtered out and washed with 1,2-dichloroethane.
The suspension of the crystals in 200 ml of chloroform and 120 ml of water was added with 5 ml of concentrated ammonia water. After the chloroform layer was dried over anhydrous sodium sulfate, it was purified by silica gel column chromatography (chloroform). By recrystallization from chloroform-n-heptane, 11.84 g of N-(5,6,7,8-tetrahydrothieno[2,3-b]-quinolin-4-yl)trichloroacetamide having the melting point of 176° to 178° C. was obtained.
In 20 ml of N-methylpyrrolidone, was dissolved 3.5 g of the obtained compound. After adding 6.2 g of ammonium acetate to the solution, the reaction was carried out at 150° C. for 30 minutes. After cooled to 30° C., the reaction mixture was added with 100 ml of water and 50 ml of chloroform, followed by stirring. The pH of the aqueous layer of the mixture was adjusted to 10 with concentrated ammonia water.
The insoluble matters were collected by filtration and washed with chloroform and water, followed by recrystallization from ethanol -1,1,2,2-tetrachloroethane-ethyl acetate to obtain 0.73 g of the titled compound having the melting point of 260° to 262° C.
In 120 ml of 1,1,2,2-tetrachloroethane, was dissolved 2.45 g of 4-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinoline, and 1.78 g of ditrichloromethyl carbonate was added to the solution at a temperature from 20° to 30° C.
After adding 6.7 g of triethylamine at a temperature from 20° to 30° C., the mixture was stirred for one hour at room temperature.
Separately, 70 ml of 40% methanol solution of methylamine was cooled at -10° C. The reaction mixture was added dropwise to the methanol solution at 0° C. and heated to 30° C. in one hour.
Then, 150 ml of water and 120 ml of chloroform were added to the mixture and the insoluble matters were filtered out, followed by recrystallization from methanol-chloroform to obtain 2.49 g of the titled compound having the melting point of 253° to 255° C.
Compounds shown in Table 4 were synthesized in the same way as in Example 31.
TABLE 4
__________________________________________________________________________
##STR136##
##STR137##
##STR138##
##STR139##
##STR140##
##STR141##
##STR142##
__________________________________________________________________________
32
##STR143##
##STR144##
H H 216˜218
33
##STR145##
##STR146##
H H 220˜235 Decomposed
34
##STR147##
##STR148##
CH.sub.3
CH.sub.3
211˜216
35
##STR149##
##STR150##
CH.sub.3
CH.sub.3
215˜218
36
##STR151##
##STR152##
H
##STR153##
248˜250
37
##STR154##
##STR155##
H H 292˜294
__________________________________________________________________________
To 5 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine, was added 22 g of L-alanine ethyl ester and the reaction was continued for 30 minutes at 100° C. After cooled to room temperature, the reaction mixture was added with 100 ml of chloroform and 100 ml of water and stirred. The chloroform layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (chloroform-methanol), followed by recrystallization from chloroform-n-hexane to obtain 5.9 g of the titled compound having the melting point of 101° to 102° C.
Into 12 ml of 1N aqueous solution of sodium hydroxide, was added 2 g of the compound obtained in Example 38 at room temperature, and the reaction was continued for 2 hours. To the reaction mixture, was added 15 ml of 1N hydrochloric acid at a temperature not higher than 15° C. to precipitate white crystals. The crystals were collected by filtration, washed with water and dried to obtain 1.42 g of the titled compound having the melting point of 238° to 242° C. (decomposed).
Compounds shown in Table 5 were synthesized in the same way as in Example 38 or 39.
TABLE 5
__________________________________________________________________________
##STR156##
##STR157##
##STR158##
##STR159##
##STR160##
##STR161##
##STR162##
__________________________________________________________________________
40
##STR163##
##STR164##
H
##STR165##
139˜140
41
##STR166##
##STR167##
H
##STR168##
127˜130
42
##STR169##
##STR170##
H
##STR171##
223˜226 Decomposed
__________________________________________________________________________
To 12.7 g of 4-amino-3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline, was added 40 ml of chloroacetyl chloride, and the mixture was refluxed for 40 minutes. The oil bath was removed and the reaction mixture was added with 50 ml of 1,2-dichloroethane and cooled to 25° C. The precipitated crystals were collected by filtration and washed with 1,2-dichloroethane. The crystals were suspended in a mixed solvent of 250 ml of chloroform, 55 ml of water and 60 ml of ethanol, and 4.3 ml of concentrated ammonia water was added thereto. The suspension was heated to 40° C. to dissolve substantially all the crystals.
The chloroform layer was dried over anhydrous sodium sulfate and concentrated to a volume of about 100 ml. The chloroform solution was added with 40 ml of n-heptane and cooled, followed by filtration to obtain 8.2 g of the titled compound having the melting point of 233° to 236° C.
To 12 ml of t-butanol and 25 ml of dimethylformamide, was added 2.1 g of the compound obtained in Reference Example 1. Then, 9 ml of cyclopropylamine was added and the reaction was carded out at 100° C. for 30 minutes.
The reaction mixture was evaporated to dryness under a reduced pressure, then, 100 ml of chloroform, 30 ml of water and 5 ml of concentrated ammonia water were added, followed by stirring. The chloroform layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (chloroform-methanol), followed by recrystallization from ethyl acetate to obtain 1.52 g of titled compound having the melting point of 141° to 144° C.
Compounds shown in Table 6 were synthesized in the same way as in Example 43.
TABLE 6
__________________________________________________________________________
##STR172##
##STR173##
##STR174##
##STR175##
##STR176##
##STR177##
__________________________________________________________________________
44
##STR178##
##STR179##
##STR180##
Amorphous solid
45
##STR181##
##STR182##
CH.sub.3 142˜145
46
##STR183##
##STR184##
##STR185##
110˜111
47
##STR186##
##STR187##
CH.sub.3 146˜149
48
##STR188##
##STR189##
CH.sub.3 141˜143
49
##STR190##
##STR191##
CH.sub.2CO.sub.2 CH.sub.3
147˜149
50
##STR192##
##STR193##
CH.sub.2CO.sub.2 H
221˜230 (Decomposed)
51
##STR194##
##STR195##
##STR196##
245˜250
52
##STR197##
##STR198##
##STR199##
218˜222
__________________________________________________________________________
In 9 ml of N-methylpyrrolidone, was dissolved 3.9 g of the compound obtained in Example 38, and 2.64 g of urea was further added thereto. The reaction was carried out at 160° C. for one hour. The reaction mixture was cooled to 80° C. and 100 ml of water was added. The precipitated crystals were collected by filtration and dissolved in a mixture of 5 ml of methanol and 150 ml of chloroform. The solution was dried over anhydrous sodium sulfate and evaporated to dryness. The obtained product was recrystallized from ethanol-ethyl acetate to obtain 2.44 g of the titled compound having the melting point of 260° to 263° C.
Compounds shown in Table 7 were synthesized in the same way as in Example 53:
TABLE 7
__________________________________________________________________________
##STR200##
##STR201##
##STR202##
##STR203##
##STR204##
##STR205##
__________________________________________________________________________
54
##STR206##
##STR207##
H 280˜287 Decomposed
55
##STR208##
##STR209##
##STR210##
219˜223
56
##STR211##
##STR212##
H 279˜283 Decomposed
57
##STR213##
##STR214##
H 285-295 Decomposed Hydrochloride
58
##STR215##
##STR216##
H 216˜263
59
##STR217##
##STR218##
H 298˜301
60
##STR219##
##STR220##
H 270˜274
__________________________________________________________________________
In 8 ml of N-methylpyrrolidone, was dissolved 2.5 g of the compound obtained in Example 44, and 8 g of urea was further added. The reaction was continued at 160° C. for 40 minutes. The reaction mixture was cooled to 80° C. and further cooled to 25° C. after addition of 90 ml of water. The precipitated crystals were collected by filtration and recrystallized from methanol-water to obtain 0.84 g of the titled compound having the melting point of 273° to 277° C.
Compound shown in Table 8 were synthesized in the same way as in Example 61.
Compounds shown in Table 9 and Table 10 can be synthesized in the same way as described in Examples above.
TABLE 8
__________________________________________________________________________
##STR221##
##STR222##
##STR223##
##STR224##
##STR225##
##STR226##
__________________________________________________________________________
62
##STR227##
##STR228##
##STR229##
197˜198
63
##STR230##
##STR231##
##STR232##
242˜245
64
##STR233##
##STR234##
##STR235##
274˜281
65
##STR236##
##STR237##
##STR238##
158˜160
__________________________________________________________________________
TABLE 9
__________________________________________________________________________
##STR239##
##STR240##
##STR241##
##STR242##
##STR243##
__________________________________________________________________________
66
##STR244##
##STR245##
##STR246##
67
##STR247##
##STR248##
C.sub.3 H.sub.7
68
##STR249##
##STR250##
C.sub.3 H.sub.7
69
##STR251##
##STR252##
C.sub.3 H.sub.7
70
##STR253##
##STR254##
C.sub.3 H.sub.7
71
##STR255##
##STR256##
C.sub.3 H.sub.7
72
##STR257##
##STR258##
C.sub.3 H.sub.7
73
##STR259##
##STR260##
C.sub.2 H.sub.5
74
##STR261##
##STR262##
##STR263##
75
##STR264##
##STR265##
C.sub.4 H.sub.9
76
##STR266##
##STR267##
##STR268##
77
##STR269##
##STR270##
##STR271##
78
##STR272##
##STR273##
C(CH.sub.3).sub.3
79
##STR274##
##STR275##
C.sub.3 H.sub.7
80
##STR276##
##STR277##
C.sub.3 H.sub.7
81
##STR278##
##STR279##
C.sub.3 H.sub.7
82
##STR280##
##STR281##
C.sub.3 H.sub.7
83
##STR282##
##STR283##
C.sub.3 H.sub.7
84
##STR284##
##STR285##
C.sub.3 H.sub.7
85
##STR286##
##STR287##
C.sub.3 H.sub.7
86
##STR288##
##STR289##
C.sub.3 H.sub.7
87
##STR290##
##STR291##
C.sub.3 H.sub.7
88
##STR292##
##STR293##
C.sub.3 H.sub.7
89
##STR294##
##STR295##
C.sub.3 H.sub.7
90
##STR296##
##STR297##
C.sub.3 H.sub.7
91
##STR298##
##STR299##
C.sub.3 H.sub.7
92
##STR300##
##STR301##
C.sub.3 H.sub.7
93
##STR302##
##STR303##
C.sub.3 H.sub.7
94
##STR304##
##STR305##
C.sub.3 H.sub.7
95
##STR306##
##STR307##
C.sub.3 H.sub.7
__________________________________________________________________________
TABLE 10
__________________________________________________________________________
##STR308##
##STR309##
##STR310##
##STR311##
##STR312##
##STR313##
##STR314##
__________________________________________________________________________
96
##STR315##
##STR316##
H C.sub.2 H.sub.5
O
97
##STR317##
##STR318##
H C.sub.3 H.sub.7
O
98
##STR319##
##STR320##
H
##STR321##
O
99
##STR322##
##STR323##
H C.sub.4 H.sub.9
O
100
##STR324##
##STR325##
H
##STR326##
O
101
##STR327##
##STR328##
H
##STR329##
O
102
##STR330##
##STR331##
H
##STR332##
O
103
##STR333##
##STR334##
H H O
104
##STR335##
##STR336##
CH.sub.3
CH.sub.3 O
105
##STR337##
##STR338##
H H O
106
##STR339##
##STR340##
CH.sub.3
CH.sub.3 O
107
##STR341##
##STR342##
CH.sub.3
CH.sub.3 O
108
##STR343##
##STR344##
H H O
109
##STR345##
##STR346##
CH.sub.3
CH.sub.3 O
110
##STR347##
##STR348##
H H O
111
##STR349##
##STR350##
H CH.sub.3 O
112
##STR351##
##STR352##
H C.sub.2 H.sub.5
O
113
##STR353##
##STR354##
H C.sub.3 H.sub.7
O
114
##STR355##
##STR356##
H
##STR357##
O
115
##STR358##
##STR359##
CH.sub.3
CH.sub.3 O
116
##STR360##
##STR361##
H H O
117
##STR362##
##STR363##
H H O
118
##STR364##
##STR365##
CH.sub.3
H O
119
##STR366##
##STR367##
CH.sub.3
CH.sub.3 O
120
##STR368##
##STR369##
H H O
121
##STR370##
##STR371##
H H O
122
##STR372##
##STR373##
H H O
123
##STR374##
##STR375##
H CH.sub.3 1
124
##STR376##
##STR377##
H CH.sub.3 1
125
##STR378##
##STR379##
H CH.sub.3 1
126
##STR380##
##STR381##
H CH.sub.3 1
127
##STR382##
##STR383##
H CH.sub.3 1
128
##STR384##
##STR385##
H CH.sub.3 1
129
##STR386##
##STR387##
H CH.sub.3 1
130
##STR388##
##STR389##
H CH.sub.3 1
131
##STR390##
##STR391##
H CH.sub.3 1
132
##STR392##
##STR393##
H CH.sub.3 1
133
##STR394##
##STR395##
H C.sub.2 H.sub.5
1
134
##STR396##
##STR397##
H C.sub.3 H.sub.7
1
135
##STR398##
##STR399##
H
##STR400##
1
136
##STR401##
##STR402##
H C.sub.4 H.sub.9
1
137
##STR403##
##STR404##
H
##STR405##
1
138
##STR406##
##STR407##
H
##STR408##
1
139
##STR409##
##STR410##
H C(CH.sub.3).sub.3
1
140
##STR411##
##STR412##
H
##STR413##
1
141
##STR414##
##STR415##
H CH.sub.3 1
142
##STR416##
##STR417##
H CH.sub.3 1
143
##STR418##
##STR419##
H CH.sub.3 1
144
##STR420##
##STR421##
H CH.sub.3 1
145
##STR422##
##STR423##
H CH.sub.3 1
146
##STR424##
##STR425##
H CH.sub.3 1
147
##STR426##
##STR427##
H CH.sub.3 1
148
##STR428##
##STR429##
H CH.sub.3 1
149
##STR430##
##STR431##
H CH.sub.3 1
150
##STR432##
##STR433##
H CH.sub.3 1
151
##STR434##
##STR435##
H CH.sub.3 1
152
##STR436##
##STR437##
H CH.sub.3 1
153
##STR438##
##STR439##
H CH.sub.3 1
154
##STR440##
##STR441##
H CH.sub.2COOC.sub.2 H.sub.5
1
155
##STR442##
##STR443##
H CH.sub.2 COOCH.sub.3
1
156
##STR444##
##STR445##
H CH.sub.2COOC.sub.2 H.sub.5
1
157
##STR446##
##STR447##
H
##STR448##
1
158
##STR449##
##STR450##
H
##STR451##
1
159
##STR452##
##STR453##
H
##STR454##
1
160
##STR455##
##STR456##
H
##STR457##
1
161
##STR458##
##STR459##
H
##STR460##
1
162
##STR461##
##STR462##
H
##STR463##
1
163
##STR464##
##STR465##
H
##STR466##
1
164
##STR467##
##STR468##
H
##STR469##
1
165
##STR470##
##STR471##
H
##STR472##
1
166
##STR473##
##STR474##
H
##STR475##
1
167
##STR476##
##STR477##
H
##STR478##
1
168
##STR479##
##STR480##
H
##STR481##
1
169
##STR482##
##STR483##
H
##STR484##
1
170
##STR485##
##STR486##
H
##STR487##
1
171
##STR488##
##STR489##
H
##STR490##
1
172
##STR491##
##STR492##
H
##STR493##
1
173
##STR494##
##STR495##
H
##STR496##
1
174
##STR497##
##STR498##
H
##STR499##
1
175
##STR500##
##STR501##
H
##STR502##
1
176
##STR503##
##STR504##
H CH.sub.2COOC.sub.2 H.sub.5
1
177
##STR505##
##STR506##
H CH.sub.2COOC.sub.2 H.sub.5
1
178
##STR507##
##STR508##
H CH.sub.2COOC.sub.2 H.sub.5
1
179
##STR509##
##STR510##
H CH.sub.2COOC.sub.2 H.sub.5
1
180
##STR511##
##STR512##
H CH.sub.2COOC.sub.2 H.sub.5
1
181
##STR513##
##STR514##
H CH.sub.2COOC.sub.2 H.sub.5
1
182
##STR515##
##STR516##
H CH.sub.2COOC.sub.2 H.sub.5
1
183
##STR517##
##STR518##
H CH.sub.2COOC.sub.2 H.sub.5
1
184
##STR519##
##STR520##
H CH.sub.2COOC.sub.2 H.sub.5
1
185
##STR521##
##STR522##
H CH.sub.2COOC.sub.2 H.sub.5
1
186
##STR523##
##STR524##
H CH.sub.2COOC.sub.2 H.sub.5
1
187
##STR525##
##STR526##
H CH.sub.2COOC.sub.2 H.sub.5
1
188
##STR527##
##STR528##
H CH.sub.2COOC.sub.2 H.sub.5
1
189
##STR529##
##STR530##
H CH.sub.2COOC.sub.2 H.sub.5
1
190
##STR531##
##STR532##
H CH.sub.2COOC.sub.2 H.sub.5
1
191
##STR533##
##STR534##
H CH.sub.2COOC.sub.2 H.sub.5
1
192
##STR535##
##STR536##
H CH.sub.2COOC.sub.2 H.sub.5
1
193
##STR537##
##STR538##
H CH.sub.2COOC.sub.2 H.sub.5
1
194
##STR539##
##STR540##
H CH.sub.2COOC.sub.2 H.sub.5
1
195
##STR541##
##STR542##
H CH.sub.2COOC.sub.2 H.sub.5
1
196
##STR543##
##STR544##
H CH.sub.2COOC.sub.2 H.sub.5
1
197
##STR545##
##STR546##
H CH.sub.2COOC.sub.2 H.sub.5
1
198
##STR547##
##STR548##
##STR549## 1
199
##STR550##
##STR551##
##STR552## 1
200
##STR553##
##STR554##
##STR555## 1
201
##STR556##
##STR557##
##STR558## 1
202
##STR559##
##STR560##
##STR561## 1
203
##STR562##
##STR563##
##STR564## 1
204
##STR565##
##STR566##
##STR567## 1
205
##STR568##
##STR569##
##STR570## 1
206
##STR571##
##STR572##
##STR573## 1
207
##STR574##
##STR575##
##STR576## 1
208
##STR577##
##STR578##
##STR579## 1
209
##STR580##
##STR581##
##STR582## 1
210
##STR583##
##STR584##
##STR585## 1
211
##STR586##
##STR587##
##STR588## 1
212
##STR589##
##STR590##
##STR591## 1
213
##STR592##
##STR593##
##STR594## 1
214
##STR595##
##STR596##
##STR597## 1
215
##STR598##
##STR599##
##STR600## 1
216
##STR601##
##STR602##
##STR603## 1
217
##STR604##
##STR605##
##STR606## 1
218
##STR607##
##STR608##
##STR609## 1
219
##STR610##
##STR611##
##STR612## 1
220
##STR613##
##STR614##
##STR615## 1
221
##STR616##
##STR617##
##STR618## 1
222
##STR619##
##STR620##
##STR621## 1
223
##STR622##
##STR623##
##STR624## 1
224
##STR625##
##STR626##
##STR627## 1
225
##STR628##
##STR629##
##STR630## 1
226
##STR631##
##STR632##
##STR633## 1
227
##STR634##
##STR635##
##STR636## 1
228
##STR637##
##STR638##
##STR639## 1
229
##STR640##
##STR641##
##STR642## 1
230
##STR643##
##STR644##
##STR645## 1
231
##STR646##
##STR647##
##STR648## 1
232
##STR649##
##STR650##
##STR651## 1
233
##STR652##
##STR653##
##STR654## 1
234
##STR655##
##STR656##
##STR657## 1
235
##STR658##
##STR659##
##STR660## 1
__________________________________________________________________________
AF64A was prepared from AF64 in accordance with the method of Fischer et al. (J. Pharmacol. Exp. Ther., 222, 140(1982)). AF64A (1.5 nmol/1.5 μl/side) was injected into both the lateral ventricles of a rat. One week after, the rat was decapitated and only the hippocampus was taken out. The hippocampus was homogenized with 0.32M of sucrose and centrifuged at 1000 g for 10 minutes. The supernatant thereof was further centrifuged at 20000 g for 20 minutes to obtain a crude synapse fraction. The crude synapse fraction was added with a compound of the present invention and incubated at 37° C. for 30 minutes. After adding [3 H]choline (1 μM), the mixture was further incubated at 37° C. for 10 minutes. Another crude synapse fraction was incubated at 37° C. for 10 minutes and used as the control. The reaction was discontinued by filtering the mixture with suction on a Whatman GF/B filter. The radioactivity on the filter was measured by a liquid scintillation counter and the measured value was regarded as the amount of HACU. The amount of protein was determined in accordance with the method of Bradford (Anal. Biochem., 72, 248(1976)). The results are shown in Table 11.
TABLE 11
______________________________________
Improvement (% base on control)
Example
No. 10.sup.-8 M
10.sup.-7 M
10.sup.-6 M
10.sup.-5 M
10.sup.-4 M
______________________________________
1 7 11 8 2 2
2 6 10 7 8 11
3 -1 13 7 23** 7
5 20** 4 18 19 --
6 3 10 4 10 --
9 0 7 5 13 --
10 11 15 26* 44** --
11 11* 10 10* 10 -1
12 14 8 17 31* --
15 3 5 7 11 -4
16 9 2 9 4 --
17 7 -1 -2 3 20
19 4 10 14 6 13
21 11* 9 11 19* 4
22 0 1 -3 10 6
25 21* 19 19* 31 22**
26 4 -3 9 14 2
27 5 18 5 18 -11
30 8 17 13 28* --
34 10* 13* -3 14 --
35 11** 17* 20** 21** -16
36 18 15 3 19* --
39 9 -7 13 16 2
41 8 8 19* 25** -4
42 1 18 17 9 -13
45 0 2 6 14 --
52 6 13 11 10 7
54 5 18** 15* 14* --
55 20** 25* 26* 36* -30
58 4 5 7 25 15
59 5 16* 22* 30* --
61 14 3 21* 25 23
63 10 13* 19 31* --
______________________________________
[*P < 0.05]-
[**P < 0.01]-
Claims (2)
1. A 4-acylaminopyridine derivative represented by the following formula (I): ##STR661## wherein R1 represents a group represented by the following formula (II): ##STR662## wherein R2 and R3 together with the nitrogen atom to which both R2 and R3 are attached represent ##STR663## wherein R6 represents a hydrogen atom or C1 -C6 alkyl group, and n represents 0 or an integer from 1 to 3; ##STR664## wherein R7 represents a hydrogen atom, C1 -C6 alkyl group or halogen atom, R8 and R9 independently represents a hydrogen atom or C1 -C4 alkyl group, R10 and R11 independently represents a hydrogen atom or C1 -C4 alkyl group; and ##STR665## wherein each of R12 and R13 independently represents a hydrogen atom or C1 -C4 alkyl group or R12 and R13 may be combined together to form a C2 -C6 alkylene group, ##STR666## and a pharmaceutically acceptable acid addition salt thereof.
2. A pharmaceutical composition comprising pharmaceutically effective amount of the 4-acylaminopyridine derivative according to claim 1 or the pharmaceutically acceptable acid addition salt according to claim 1, and a pharmaceutically acceptable adjuvant.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/355,181 US5536728A (en) | 1989-11-08 | 1994-12-08 | 4-acylaminopyridine derivative |
| US08/629,901 US5861411A (en) | 1989-11-08 | 1996-04-10 | 4-Acylaminopyridine derivative |
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1-290915 | 1989-11-08 | ||
| JP1290916A JP2720549B2 (en) | 1989-11-08 | 1989-11-08 | 9-aminoacetylaminotetrahydroacridine derivative |
| JP1-290916 | 1989-11-08 | ||
| JP1-290918 | 1989-11-08 | ||
| JP29091889 | 1989-11-08 | ||
| JP29091589 | 1989-11-08 | ||
| US61005990A | 1990-11-07 | 1990-11-07 | |
| US85351992A | 1992-03-18 | 1992-03-18 | |
| US08/115,257 US5397785A (en) | 1989-11-08 | 1993-09-02 | 4-acylaminopyridine derivative |
| US08/355,181 US5536728A (en) | 1989-11-08 | 1994-12-08 | 4-acylaminopyridine derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US08/115,257 Division US5397785A (en) | 1989-11-08 | 1993-09-02 | 4-acylaminopyridine derivative |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US08/629,901 Division US5861411A (en) | 1989-11-08 | 1996-04-10 | 4-Acylaminopyridine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US5536728A true US5536728A (en) | 1996-07-16 |
Family
ID=27337617
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US08/115,257 Expired - Lifetime US5397785A (en) | 1989-11-08 | 1993-09-02 | 4-acylaminopyridine derivative |
| US08/355,181 Expired - Lifetime US5536728A (en) | 1989-11-08 | 1994-12-08 | 4-acylaminopyridine derivative |
| US08/629,901 Expired - Lifetime US5861411A (en) | 1989-11-08 | 1996-04-10 | 4-Acylaminopyridine derivative |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US08/115,257 Expired - Lifetime US5397785A (en) | 1989-11-08 | 1993-09-02 | 4-acylaminopyridine derivative |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US08/629,901 Expired - Lifetime US5861411A (en) | 1989-11-08 | 1996-04-10 | 4-Acylaminopyridine derivative |
Country Status (9)
| Country | Link |
|---|---|
| US (3) | US5397785A (en) |
| EP (1) | EP0427636B1 (en) |
| KR (1) | KR100192833B1 (en) |
| AT (1) | ATE138653T1 (en) |
| CA (1) | CA2029497C (en) |
| DE (1) | DE69027180T2 (en) |
| DK (1) | DK0427636T3 (en) |
| ES (1) | ES2088998T3 (en) |
| GR (1) | GR3020868T3 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040235884A1 (en) * | 2001-08-06 | 2004-11-25 | Ken Takashina | Preventives/remedies for cholinergic neuropathy |
| US7998971B2 (en) | 2006-09-08 | 2011-08-16 | Braincells Inc. | Combinations containing a 4-acylaminopyridine derivative |
| US8003632B2 (en) | 2004-01-27 | 2011-08-23 | The Feinstein Institute For Medical Research | Cholinesterase inhibitors for treating inflammation |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR0126300B1 (en) * | 1992-12-28 | 1997-12-26 | 나이토 하루오 | Heterocyclic carbonic acid derivatives which bind to retinoid receptors |
| US5852041A (en) * | 1993-04-07 | 1998-12-22 | Sibia Neurosciences, Inc. | Substituted pyridines useful as modulators of acethylcholine receptors |
| JPH0892100A (en) * | 1994-09-21 | 1996-04-09 | Mitsubishi Chem Corp | Therapeutic medicine and preventive for nervous system trouble |
| US5585388A (en) * | 1995-04-07 | 1996-12-17 | Sibia Neurosciences, Inc. | Substituted pyridines useful as modulators of acetylcholine receptors |
| US5794887A (en) | 1995-11-17 | 1998-08-18 | Komerath; Narayanan M. | Stagnation point vortex controller |
| TWI332503B (en) | 2001-04-19 | 2010-11-01 | Mitsubishi Tanabe Pharma Corp | Polymorph forms of n-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide |
| US7332508B2 (en) * | 2002-12-18 | 2008-02-19 | Novo Nordisk A/S | Substituted homopiperidine, piperidine or pyrrolidine derivatives |
| US20060173031A1 (en) * | 2003-01-08 | 2006-08-03 | Mitsubishi Pharma Corporation | Therapeutic agent for schizophrenia |
| CA2641659A1 (en) * | 2006-02-07 | 2007-02-06 | Mitsubishi Tanabe Pharma Corporation | 4-acylaminopyridine derivative mediated neurogenesis |
| JP2012514594A (en) * | 2009-01-05 | 2012-06-28 | カウンシル オブ サイエンティフィック アンド インダストリアル リサーチ | Thienopyridine as a pharmacologically active drug |
| MX2012006580A (en) * | 2009-12-11 | 2012-09-28 | Genecode As | Methods of facilitating neural cell survival using gdnf family ligand (gfl) mimetics or ret signaling pathway activators. |
| CN102219740B (en) * | 2010-09-10 | 2013-02-13 | 长春华洋高科技有限公司 | 1,2,3,4,5,6,7,8-octahydro-9-phenylacetamide acridine as well as preparation method and medicinal application thereof |
| CZ309262B6 (en) * | 2021-01-26 | 2022-06-29 | Fakultní nemocnice Hradec Králové | Dual active tacrine derivatives and their use |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0273176A2 (en) * | 1986-11-24 | 1988-07-06 | Hoechst-Roussel Pharmaceuticals Incorporated | Fused heterocyclic tetrahydroaminoquinolinols and related compounds, a process for their preparation and their use as medicaments |
| WO1989002740A1 (en) * | 1987-10-05 | 1989-04-06 | Pfizer Inc. | 4-aminopyridine derivatives |
| EP0319429A2 (en) * | 1987-12-03 | 1989-06-07 | Mitsubishi Kasei Corporation | 9-Acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient |
| US4880819A (en) * | 1987-09-17 | 1989-11-14 | Mitsubishi Kasei Corporation | 4-aminopyridine derivatives for improving impaired brain function |
| EP0411534A2 (en) * | 1989-07-31 | 1991-02-06 | Warner-Lambert Company | Derivatives of 1,2,3,4-tetrahydro-9-acridinamine |
-
1990
- 1990-11-07 CA CA002029497A patent/CA2029497C/en not_active Expired - Lifetime
- 1990-11-08 KR KR1019900018017A patent/KR100192833B1/en not_active IP Right Cessation
- 1990-11-08 EP EP90403182A patent/EP0427636B1/en not_active Expired - Lifetime
- 1990-11-08 DK DK90403182.0T patent/DK0427636T3/en active
- 1990-11-08 ES ES90403182T patent/ES2088998T3/en not_active Expired - Lifetime
- 1990-11-08 DE DE69027180T patent/DE69027180T2/en not_active Expired - Lifetime
- 1990-11-08 AT AT90403182T patent/ATE138653T1/en not_active IP Right Cessation
-
1993
- 1993-09-02 US US08/115,257 patent/US5397785A/en not_active Expired - Lifetime
-
1994
- 1994-12-08 US US08/355,181 patent/US5536728A/en not_active Expired - Lifetime
-
1996
- 1996-04-10 US US08/629,901 patent/US5861411A/en not_active Expired - Lifetime
- 1996-08-22 GR GR960402226T patent/GR3020868T3/en unknown
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0273176A2 (en) * | 1986-11-24 | 1988-07-06 | Hoechst-Roussel Pharmaceuticals Incorporated | Fused heterocyclic tetrahydroaminoquinolinols and related compounds, a process for their preparation and their use as medicaments |
| US4880819A (en) * | 1987-09-17 | 1989-11-14 | Mitsubishi Kasei Corporation | 4-aminopyridine derivatives for improving impaired brain function |
| WO1989002740A1 (en) * | 1987-10-05 | 1989-04-06 | Pfizer Inc. | 4-aminopyridine derivatives |
| EP0319429A2 (en) * | 1987-12-03 | 1989-06-07 | Mitsubishi Kasei Corporation | 9-Acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient |
| US4985430A (en) * | 1987-12-03 | 1991-01-15 | Mitsubishi Kasei Corporation | 9-acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient |
| EP0411534A2 (en) * | 1989-07-31 | 1991-02-06 | Warner-Lambert Company | Derivatives of 1,2,3,4-tetrahydro-9-acridinamine |
Non-Patent Citations (2)
| Title |
|---|
| G. M. Steinberg et al., "A Hydrophobic Binding Site In Acetylcholinesterase", Journal of Medicinal Chemistry, Nov. 1975, pp. 1056-1061. |
| G. M. Steinberg et al., A Hydrophobic Binding Site In Acetylcholinesterase , Journal of Medicinal Chemistry, Nov. 1975, pp. 1056 1061. * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040235884A1 (en) * | 2001-08-06 | 2004-11-25 | Ken Takashina | Preventives/remedies for cholinergic neuropathy |
| US8003632B2 (en) | 2004-01-27 | 2011-08-23 | The Feinstein Institute For Medical Research | Cholinesterase inhibitors for treating inflammation |
| US7998971B2 (en) | 2006-09-08 | 2011-08-16 | Braincells Inc. | Combinations containing a 4-acylaminopyridine derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| US5397785A (en) | 1995-03-14 |
| DK0427636T3 (en) | 1996-10-14 |
| CA2029497C (en) | 2002-06-04 |
| EP0427636A3 (en) | 1991-11-06 |
| EP0427636A2 (en) | 1991-05-15 |
| DE69027180D1 (en) | 1996-07-04 |
| ATE138653T1 (en) | 1996-06-15 |
| EP0427636B1 (en) | 1996-05-29 |
| DE69027180T2 (en) | 1997-01-09 |
| US5861411A (en) | 1999-01-19 |
| CA2029497A1 (en) | 1991-05-09 |
| KR910009667A (en) | 1991-06-28 |
| GR3020868T3 (en) | 1996-11-30 |
| ES2088998T3 (en) | 1996-10-01 |
| KR100192833B1 (en) | 1999-06-15 |
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